Case Report: Early Distant Metastatic Inflammatory Myofibroblastic Tumor Harboring EML4-ALK Fusion Gene: Study of Two Typical Cases and Review of Literature.

Qianqian Han,Yan Qiu,Yuli Li,Huijiao Chen,Hongying Zhang,Lijuan Cui,Xin He

doi:10.3389/fmed.2022.826705

Abstract

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm that frequently arises in the lung and accounts for ~1% of lung tumors. Distant metastatic IMT is extremely rare and has been poorly investigated. This analysis was specifically performed to explore the clinicopathological and genetic features of early distant metastatic IMT. Two typical patients with distant metastatic IMTs were selected, which accounted for 1.13% of all diagnosed IMTs in the last 5 years. One patient was a 55 year-old male, and the other patient was a 56 year-old female. Both primary tumors arose from the lung, and the initial clinical symptoms of the two patients involved coughing. Both of the imaging examinations showed low-density nodular shadows in the lungs with enhancement around the mass. Microscopically, dense arranged tumor cells, prominent cellular atypia, and high mitotic activity with atypical form were more prominent in the metastatic lesions than in the primary lesions. All of the primary and metastatic tumors in both cases showed positive anaplastic lymphoma kinase (ALK) immunostaining and ALK rearrangement via fluorescence in situ hybridization. The EML4 (exon 6)-ALK (exon 20) fusion variant (v3a/b) was identified by using next-generation sequencing (NGS) and was verified by using reverse transcription polymerase chain reaction (RT-PCR). Furthermore, intronic variants of NOTCH1 and synonymous variants of ARAF were also detected via NGS in one IMT for the first time and were verified in all of the primary and metastatic lesions via PCR. Distant metastasis occurred during a short period of time (1 and 2 months) after the first surgery. One patient presented with multiple metastases to the subcutaneous tissue and bone that responded to ALK inhibitor alectinib therapy, and the tumor was observed to regress 10 months after the initial ALK inhibitor therapy. In contrast, the other patient presented with subcutaneous neck metastasis without ALK inhibitor treatment and succumbed to the disease within 3 months after the surgery. This study demonstrated the possible role of EML4-ALKv3a/b in the malignant progression of IMT and proposed certain therapeutic effects of ALK inhibitors on multiple metastatic IMTs.

Highlights

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by chronic inflammatory infiltration [1]
We present two cases of metastatic IMTs, harboring EML4ALK fusion, and review the literature to summarize the clinicopathological and genetic features that may help to predict the tendency of metastasis in IMT
A search of the English literature indicated that approximately 50 metastatic

Summary

INTRODUCTION

Inflammatory myofibroblastic tumor (IMT) is a distinctive neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by chronic inflammatory infiltration [1]. In case 1, the metastatic lesion of the left neck was found and grew rapidly to 3 cm 1 month after the initial surgery, and it was resected (Figure 1b). Hematoxylin and eosin staining (H&E) was performed on all of the primary and metastatic lesions (Figure 2). ALK-IHC showed diffuse cytoplasmic reactivity in all 5 specimens (Figure 2g), and the density in the metastatic lesions was higher than that in the primary lesions. Subsequent NGS broad molecular profiling of the tumor tissue was performed, and the fusion break-point involved exon 6 of EML4 and exon 20 of ALK in all of the primary and metastatic tumors of these cases with identical fusion sequences. The patient is still in good clinical condition without adverse events 16 months after the initiation of alectinib treatment

DISCUSSION

Findings

ETHICS STATEMENT